Asenapine, trademark Saphris®, chemically trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, in sublingual dissolving tablet form, has been approved in the US in August 2009 for the acute treatment of adult patients with schizophrenia and as monotherapy for acute mania or mixed episodes associated with bipolar disorders. The FDA has recently approved its use as ongoing maintenance treatment for schizophrenia and as adjunctive therapy with lithium or with valproate for bipolar 1 disorder.
Certain crystalline addition salts of Asenapine, for instance a fumarate (EP 0569096), salts with sulfonic acids (WO98/54186), and a pamoate or hemipamoate salt (EP569096), are described in the literature. The pamoate salt is disclosed to be amorphous and the hemipamoate salt is a mixture of amorphous and crystalline phase, wherein the palmitate is described as oil. The marketed form is the maleate salt, which is disclosed to exist in polymorphic forms (WO 2006/106135). The known Asenapine salts have a low solubility in water. For example, Funke et. al. (Arzneim.-Forsch./Drug Res. 40, 1999, 536-539) reports that a saturated solution of the maleate salt of Asenapine at 23° C. has a concentration of 5.8 mg/ml at pH=4.4 (see also US2008/0306133 A1 regarding the solubility of Asenapine. This translates into a free base solubility of about 4.1 mg/ml. WO2009/135091 also discloses Asenapine and related compounds and salts thereof for treating a neuronal or non-neuronal indication. Peter van Hoof et al. (Amorphous Pharmaceutical Materials, September 2009, Amsterdam) describe a method for validation of a drug product of Asenapine in solid state form.
The discovery of new salts of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example a pharmaceutical dosage form of a drug with targeted release profile or other desired characteristic.
A further aspect of the invention is to provide new forms of Asenapine with a smaller tendency towards formation of polymorphic forms. Polymorphism is well known in the pharmaceutical industry and active pharmaceutical ingredients (API) that exist in multiple crystalline forms (polymorphs) are generally undesired, because different polymorphs exhibit different physico-chemical properties, and in particular, if a solubility difference between two polymorphs is found this may have a direct impact on the bioavailability. As a consequence, if an API exists in multiple crystalline forms, greater efforts are often necessary to control the manufacturing process, to develop analytical methods, to set-up additional specifications and controls to guarantee the safety and consistency during the shelf-life of the drug product. This increases the costs for the end product. It is therefore highly desirable to provide Asenapine in a form that shows a good solubility and bioavailability profile as well as stability, e.g. against a potential phase conversion.
Furthermore, a premise for a sublingual dissolving tablet form is an active ingredient exhibiting good solubility in a fast dissolving matrix. It is an objective of the invention to provide pharmaceutically acceptable forms of Asenapine that may have a good solubility. It is also an object of the invention to provide Asenapine in a form that may have a good chemical and/or physical stability and/or good processability, both during its preparation and in the preparation of pharmaceutical compositions containing Asenapine.